Deacetylase inhibitors

ABSTRACT

The present invention provides hydroxamate compounds which are deacetylase inhibitors. The compounds are suitable for pharmaceutical compositions having anti-proliferative properties.

[0001] The present invention relates to hydroxamate compounds which areinhibitors of histone deacetylase. The inventive compounds are useful aspharmaceuticals for the treatment of proliferative diseases.

BACKGROUND

[0002] Reversible acetylation of histones is a major regulator of geneexpression that acts by altering accessibility of transcription factorsto DNA. In normal cells, histone deacetylase (HDA) and histoneacetyltrasferase together control the level of acetylation of histonesto maintain a balance. Inhibition of HDA results in the accumulation ofhyperacetylated histones, which results in a variety of cellularresponses.

[0003] Inhibitors of HDA have been studied for their therapeutic effectson cancer cells. For example, butyric acid and its derivatives,including sodium phenylbutyrate, have been reported to induce apoptosisin vitro in human colon carcinoma, leukemia and retinoblastoma celllines. However, butyric acid and its derivatives are not usefulpharmacological agents because they tend to be metabolized rapidly andhave a very short half-life in vivo. Other inhibitors of HDA that havebeen widely studied for their anti-cancer activities are trichostatin Aand trapoxin. Trichostatin A is an antifungal and antibiotic and is areversible inhibitor of mammalian HDA. Trapoxin is a cyclictetrapeptide, which is an irreversible inhibitor of mammalian HDA.Although trichostatin and trapoxin have been studied for theiranti-cancer activities, the in vivo instability of the compounds makesthem less suitable as anti-cancer drugs. There remains a need for anactive compound that is suitable for treating tumors, includingcancerous tumors, that is highly efficacious and stable.

SUMMARY

[0004] The present invention provides efficacious deacetylase inhibitorcompounds that are useful as pharmaceutical agents having the formula(I):

[0005] wherein

[0006] R₁ is H, halo, or a straight chain C₁-C₆ alkyl (especiallymethyl, ethyl or n-propyl, which methyl, ethyl and n-propyl substituentsare unsubstituted or substituted by one or more substituents describedbelow for alkyl substituents);

[0007] R₂ is selected from H, C₁-C₁₀ alkyl, (e.g. methyl, ethyl or—CH₂CH₂—OH), C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl, C₄-C₉heterocycloalkylalkyl, cycloalkylalkyl (e.g., cyclopropylmethyl), aryl,heteroaryl, arylalkyl (e.g. benzyl), heteroarylalkyl (e.g.pyridylmethyl), —(CH₂)_(n)C(O)R₆, —(CH₂)_(n)OC(O)R₆, amino acyl,HON—C(O)—CH═C(R₁)-aryl-alkyl- and —(CH₂)_(n)R₇;

[0008] R₃ and R₄ are the same or different and independently H, C₁-C₆alkyl, acyl or acylamino, or R₃ and R₄ together with the carbon to whichthey are bound represent C═O, C═S, or C═NR₈, or R₂ together with thenitrogen to which it is bound and R₃ together with the carbon to whichit is bound can form a C₄-C₉ heterocycloalkyl, a heteroaryl, apolyheteroaryl, a non-aromatic polyheterocycle, or a mixed aryl andnon-aryl polyheterocycle ring;

[0009] R₅ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉heterocycloalkyl, acyl, aryl, heteroaryl, arylalkyl (e.g. benzyl),heteroarylalkyl (e.g. pyridylmethyl), aromatic polycycles, non-aromaticpolycycles, mixed aryl and non-aryl polycycles, polyheteroaryl,non-aromatic polyheterocycles, and mixed aryl and non-arylpolyheterocycles;

[0010] n, n₁, n₂ and n₃ are the same or different and independentlyselected from 0-6, when n, is 1-6, each carbon atom can be optionallyand independently substituted with R₃ and/or R₄;

[0011] X and Y are the same or different and independently selected fromH, halo, C₁-C₄ alkyl, such as CH₃ and CF₃, NO₂, C(O)R₁, OR₉, SR₉, CN,and NR₁₀R₁₁;

[0012] R₆ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉heterocycloalkyl, cycloalkylalkyl (e.g., cyclopropylmethyl), aryl,heteroaryl, arylalkyl (e.g., benzyl, 2-phenylethenyl), heteroarylalkyl(e.g., pyridylmethyl), OR₁₂, and NR₁₃R₄;

[0013] R₇ is selected from OR₁₅, SR₁₅, S(O)R₁₆, SO₂R₁₇, NR₁₃R₁₄, andNR₁₂SO₂R₆;

[0014] R₈ is selected from H, OR₁₅, NR₁₃R₁₄, C₁-C₆ alkyl, C₄-C₉cycloalkyl, C₄-C₉ heterocycloalkyl, aryl, heteroaryl, arylalkyl (e.g.,benzyl), and heteroarylalkyl (e.g., pyridylmethyl);

[0015] R₉ is selected from C₁-C₄ alkyl, for example, CH₃ and CF₃,C(O)-alkyl, for example C(O)CH₃, and C(O)CF₃;

[0016] R₁₀ and R₁₁ are the same or different and independently selectedfrom H, C₁-C₄ alkyl, and —C(O)-alkyl;

[0017] R₁₂ is selected from H, C₁-C₆ alkyl, C₄ -C₉ cycloalkyl, C₄-C₉heterocycloalkyl, C₄-C₉ heterocycloalkylalkyl, aryl, mixed aryl andnon-aryl polycycle, heteroaryl, arylalkyl (e.g., benzyl), andheteroarylalkyl (e.g., pyridylmethyl);

[0018] R₁₃ and R₁₄ are the same or different and independently selectedfrom H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl, aryl,heteroaryl, arylalkyl (e.g., benzyl), heteroarylalkyl (e.g.,pyridylmethyl), amino acyl, or R₁₃ and R₁₄ together with the nitrogen towhich they are bound are C₄-C₉ heterocycloalkyl, heteroaryl,polyheteroaryl, non-aromatic polyheterocycle or mixed aryl and non-arylpolyheterocycle;

[0019] R₁₅ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and(CH₂)_(m)ZR₁₂;

[0020] R₁₆ is selected from C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉heterocycloalkyl, aryl, heteroaryl, polyheteroaryl, arylalkyl,heteroarylalkyl and (CH₂)_(m)ZR₁₂;

[0021] R₁₇ is selected from C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉heterocycloalkyl, aryl, aromatic polycycles, heteroaryl, arylalkyl,heteroarylalkyl, polyheteroaryl and NR₁₃R₁₄;

[0022] m is an integer selected from 0 to 6; and

[0023] Z is selected from O, NR₁₃, S and S(O),

[0024] or a pharmaceutically acceptable salt thereof.

[0025] The compounds of the present invention are suitable as activeagents in pharmaceutical compositions that are efficacious particularlyfor treating cellular proliferative ailments. The pharmaceuticalcomposition has a pharmaceutically effective amount of the presentactive agent along with other pharmaceutically acceptable exicipients,carriers, fillers, diluents and the like. The term pharmacueticallyeffective amount as used herein indicates an amount necessary toadminister to a host to achieve a therapeutic result, especially ananti-tumor effect, e.g., inhibition of proliferation of malignant cancercells, benign tumor cells or other proliferative cells.

DETAILED DESCRIPTION

[0026] The present invention provides hydroxamate compounds, e.g.,hydroxamic acids, that are inhibitors of deacetylases, preferablyinhibitors of histone deacetylases. The hydroxamate compounds are highlysuitable for treating tumors, including cancerous tumors. Thehydroxamate compounds of the present invention have the followingstructure (I):

[0027] wherein

[0028] R₁ is H, halo, or a straight chain C₁-C₆ alkyl (especiallymethyl, ethyl or n-propyl, which methyl, ethyl and n-propyl substituentsare unsubstituted or substituted by one or more substituents describedbelow for alkyl substituents);

[0029] R₂ is selected from H, C₁-C₁₀ alkyl, (preferably C₁-C₆ alkyl,e.g. methyl, ethyl or —CH₂CH₂—OH), C₄-C₉ cycloalkyl, C₄-C₉heterocycloalkyl, C₄-C₉ heterocycloalkylalkyl, cycloalkylalkyl (e.g.,cyclopropylmethyl), aryl, heteroaryl, arylalkyl (e.g. benzyl),heteroarylalkyl (e.g. pyridylmethyl), —(CH₂)_(n)C(O)R₆,—(CH₂)_(n)OC(O)R₆, amino acyl, HON—C(O)—CH═C(R₁)-aryl-alkyl- and—(CH₂)_(n)R₇;

[0030] R₃ and R₄ are the same or different and independently H, C₁-C₆alkyl, acyl or acylamino, or R₃ and R₄ together with the carbon to whichthey are bound represent C═O, C═S, or C═NR₈, or R₂ together with thenitrogen to which it is bound and R₃ together with the carbon to whichit is bound can form a C₄-C₉ heterocycloalkyl, a heteroaryl, apolyheteroaryl, a non-aromatic polyheterocycle, or a mixed aryl andnon-aryl polyheterocycle ring;

[0031] R₅ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉heterocycloalkyl, acyl, aryl, heteroaryl, arylalkyl (e.g. benzyl),heteroarylalkyl (e.g. pyridylmethyl), aromatic polycycles, non-aromaticpolycycles, mixed aryl and non-aryl polycycles, polyheteroaryl,non-aromatic polyheterocycles, and mixed aryl and non-arylpolyheterocycles;

[0032] n, n₁, n₂ and n₃ are the same or different and independentlyselected from 0-6, when n, is 1-6, each carbon atom can be optionallyand independently substituted with R₃ and/or R₄;

[0033] X and Y are the same or different and independently selected fromH, halo, C₁-C₄ alkyl, such as CH₃ and CF₃, NO₂, C(O)R,, OR₉, SR₉, CN,and NR₁₀R₁₁;

[0034] R₆ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉heterocycloalkyl, cycloalkylalkyl (e.g., cyclopropylmethyl), aryl,heteroaryl, arylalkyl (e.g., benzyl, 2-phenylethenyl), heteroarylalkyl(e.g., pyridylmethyl), OR₁₂, and NR₁₃R₁₄;

[0035] R₇ is selected from OR₁₅, SR₁₅, S(O)R₁₆, SO₂R₁₇, NR₁₃R₁₄, andNR₁₂SO₂R₆;

[0036] R₈ is selected from H, OR₁₅, NR₁₃R₁₄, C₁-C₆ alkyl, C₄-C₉cycloalkyl, C₄-C₉ heterocycloalkyl, aryl, heteroaryl, arylalkyl (e.g.,benzyl), and heteroarylalkyl (e.g., pyridylmethyl);

[0037] R₉ is selected from C₁-C₄ alkyl, for example, CH₃ and CF₃,C(O)-alkyl, for example C(O)CH₃, and C(O)CF₃;

[0038] R₁₀ and R₁, are the same or different and independently selectedfrom H, C₁-C₄ alkyl, and —C(O)-alkyl;

[0039] R₁₂ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉heterocycloalkyl, C₄-C₉ heterocycloalkylalkyl, aryl, mixed aryl andnon-aryl polycycle, heteroaryl, arylalkyl (e.g., benzyl), andheteroarylalkyl (e.g., pyridylmethyl);

[0040] R₁₃ and R₁₄ are the same or different and independently selectedfrom H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl, aryl,heteroaryl, arylalkyl (e.g., benzyl), heteroarylalkyl (e.g.,pyridylmethyl), amino acyl, or R₁₃ and R₁₄ together with the nitrogen towhich they are bound are C₄-C₉ heterocycloalkyl, heteroaryl,polyheteroaryl, non-aromatic polyheterocycle or mixed aryl and non-arylpolyheterocycle;

[0041] R₁₅ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and(CH₂)_(m)ZR₁₂;

[0042] R₁₆ is selected from C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉heterocycloalkyl, aryl, heteroaryl, polyheteroaryl, arylalkyl,heteroarylalkyl and (CH₂)_(m)ZR₁₂;

[0043] R₁₇ is selected from C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉heterocycloalkyl, aryl, aromatic polycycles, heteroaryl, arylalkyl,heteroarylalkyl, polyheteroaryl and NR₁₃R₁₄;

[0044] m is an integer selected from 0 to 6; and

[0045] Z is selected from O, NR₁₃, S and S(O),

[0046] or a pharmaceutically acceptable salt thereof.

[0047] As appropriate, unsubstituted means that there is no substituentor that the only substituents are hydrogen.

[0048] Halo substituents are selected from fluoro, chloro, bromo andiodo, preferably fluoro or chloro.

[0049] Alkyl substituents include straight and branched C₁-C₆alkyl,unless otherwise noted. Examples of suitable straight and branchedC₁-C₆alkyl substituents include methyl, ethyl, n-propyl, 2-propyl,n-butyl, sec-butyl, t-butyl, and the like. Unless otherwise noted, thealkyl substituents include both unsubstituted alkyl groups and alkylgroups that are substituted by one or more suitable substituents,including unsaturation (i.e. there are one or more double or triple C—Cbonds), acyl, cycloalkyl, halo, oxyalkyl, alkylamino, aminoalkyl,acylamino and OR₁₅, for example, alkoxy. Preferred substituents foralkyl groups include halo, hydroxy, alkoxy, oxyalkyl, alkylamino, andaminoalkyl.

[0050] Cycloalkyl substituents include C₃-C₉ cycloalkyl groups, such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unlessotherwise specified. Unless otherwise noted, cycloalkyl substituentsinclude both unsubstituted cycloalkyl groups and cycloalkyl groups thatare substituted by one or more suitable substituents, including C₁-C₆alkyl, halo, hydroxy, aminoalkyl, oxyalkyl, alkylamino, and OR₁₅, suchas alkoxy. Preferred substituents for cycloalkyl groups include halo,hydroxy, alkoxy, oxyalkyl, alkylamino and aminoalkyl.

[0051] The above discussion of alkyl and cycloalkyl substituents alsoapplies to the alkyl portions of other substituents, such as withoutlimitation, alkoxy, alkyl amines, alkyl ketones, arylalkyl,heteroarylalkyl, alkylsulfonyl and alkyl ester substituents and thelike.

[0052] Heterocycloalkyl substituents include 3 to 9 membered aliphaticrings, such as 4 to 7 membered aliphatic rings, containing from one tothree heteroatoms selected from nitrogen, sulfur, oxygen. Examples ofsuitable heterocycloalkyl substituents include pyrrolidyl,tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl,tetrahydropyranyl, morphilino, 1,3-diazapane, 1,4-diazapane,1,4-oxazepane, and 1,4-oxathiapane. Unless otherwise noted, the ringsare unsubstituted or substuted on the carbon atoms by one or moresuitable substituents, including C₁-C₆ alkyl, C₄-C₉ cycloalkyl, aryl,heteroaryl, arylalkyl (e.g., benzyl), and heteroarylalkyl (e.g.,pyridylmethyl), halo, amino, alkyl amino and OR₁₅, for example alkoxy.Unless otherwise noted, nitrogen heteroatoms are unsubstituted orsubstituted by H, C₁-C₄ alkyl, arylalkyl (e.g., benzyl), andheteroarylalkyl (e.g., pyridylmethyl), acyl, aminoacyl, alkylsulfonyl,and arylsulfonyl.

[0053] Cycloalkylalkyl substituents include compounds of the formula—(CH₂)_(n5)-cycloalkyl wherein n5 is a number from 1-6. Suitablealkylcycloalkyl substituents include cyclopentylmethyl-,cyclopentylethyl, cyclohexylmethyl and the like. Such substituents areunsubstituted or substituted in the alkyl portion or in the cycloalkylportion by a suitable substituent, including those listed above foralkyl and cycloalkyl.

[0054] Aryl substituents include unsubstituted phenyl and phenylsubstituted by one or more suitable substituents, including C₁-C₆ alkyl,cycloalkylalkyl (e.g., cyclopropylmethyl), O(CO)alkyl, oxyalkyl, halo,nitro, amino, alkylamino, aminoalkyl, alkyl ketones, nitrile,carboxyalkyl, alkylsulfonyl, aminosulfonyl, arylsulfonyl, and OR₁₅, suchas alkoxy. Preferred substituents include including C₁-C₆ alkyl,cycloalkyl (e.g., cyclopropylmethyl), alkoxy, oxyalkyl, halo, nitro,amino, alkylamino, aminoalkyl, alkyl ketones, nitrile, carboxyalkyl,alkylsulfonyl, arylsulfonyl, and aminosulfonyl. Examples of suitablearyl groups include C₁-C₄alkylphenyl, C₁-C₄alkoxyphenyl,trifluoromethylphenyl, methoxyphenyl, hydroxyethylphenyl,dimethylaminophenyl, aminopropylphenyl, carbethoxyphenyl,methanesulfonylphenyl and tolylsulfonylphenyl.

[0055] Aromatic polycycles include naphthyl, and naphthyl substituted byone or more suitable substituents, including C₁-C₆ alkyl,alkylcycloalkyl (e.g., cyclopropylmethyl), oxyalkyl, halo, nitro, amino,alkylamino, aminoalkyl, alkyl ketones, nitrile, carboxyalkyl,alkylsulfonyl, arylsulfonyl, aminosulfonyl and OR₁₅, such as alkoxy.

[0056] Heteroaryl substituents include compounds with a 5 to 7 memberaromatic ring containing 5- one or more heteroatoms, for example from 1to 4 heteroatoms, selected from N, O and S. Typical heteroarylsubstituents include furyl, thienyl, pyrrole, pyrazole, triazole,thiazole, oxazole, pyridine, pyrimidine, isoxazolyl, pyrazine and thelike. Unless otherwise noted, heteroaryl substituents are unsubstitutedor substituted on a carbon atom by one or more suitable substituents,including alkyl, the alkyl substituents identified above, and anotherheteroaryl substituent. Nitrogen atoms are unsubstituted or substituted,for example by R₁₃; especially useful N substituents include H, C₁-C₄alkyl, acyl, aminoacyl, and sulfonyl.

[0057] Arylalkyl substituents include groups of the formula—(CH₂)_(n5)-aryl, —(CH₂)_(n5-1)(CHaryl)—(CH₂)_(n5)-aryl or—(CH₂)_(n5-1)CH(aryl)(aryl) wherein aryl and n5 are defined above. Sucharylalkyl substituents include benzyl, 2-phenylethyl, 1-phenylethyl,tolyl-3-propyl, 2-phenylpropyl, diphenylmethyl, 2-diphenylethyl,5,5-dimethyl-3-phenylpentyl and the like. Arylalkyl substituents areunsubstituted or substituted in the alkyl moiety or the aryl moiety orboth as described above for alkyl and aryl substituents.

[0058] Heteroarylalkyl substituents include groups of the formula—(CH₂)_(n5)-heteroaryl wherein heteroaryl and n5 are defined above andthe bridging group is linked to a carbon or a nitrogen of the heteroarylportion, such as 2-, 3- or 4-pyridylmethyl, imidazolylmethyl,quinolylethyl, and pyrrolylbutyl. Heteroaryl substituents areunsubstituted or substituted as discussed above for heteroaryl and alkylsubstituents.

[0059] Amino acyl substituents include groups of the formula—C(O)—(CH₂)_(n)—C(H)(NR₁₃R₁₄)—(CH₂)_(n)—R₅ wherein n, R₁₃, R₁₄ and R₅are described above. Suitable aminoacyl substituents include natural andnon-natural amino acids such as glycinyl, D-tryptophanyl, L-lysinyl, D-or L-homoserinyl, 4-aminobutryic acyl, ±-3-amin-4-hexenoyl.

[0060] Non-aromatic polycycle substituents include bicyclic andtricyclic fused ring systems where each ring can be 4-9 membered andeach ring can contain zero, 1 or more double and/or triple bonds.Suitable examples of non-aromatic polycycles include decalin,octahydroindene, perhydrobenzocycloheptene, perhydrobenzo-[f]-azulene.Such substituents are unsubstituted or substituted as described abovefor cycloalkyl groups.

[0061] Mixed aryl and non-aryl polycycle substituents include bicyclicand tricyclic fused ring systems where each ring can be 4-9 membered andat least one ring is aromatic. Suitable examples of mixed aryl andnon-aryl polycycles include methylenedioxyphenyl,bis-methylenedioxyphenyl, 1,2,3,4-tetrahydronaphthalene,dibenzosuberane, dihdydroanthracene, 9H-fluorene. Such substituents areunsubstituted or substituted by nitro or as described above forcycloalkyl groups.

[0062] Polyheteroaryl substituents include bicyclic and tricyclic fusedring systems where each ring can independently be 5 or 6 membered andcontain one or more heteroatom, for example, 1, 2, 3, or 4 heteroatoms,chosen from O, N or S such that the fused ring system is aromatic.Suitable examples of polyheteroaryl ring systems include quinoline,isoquinoline, pyridopyrazine, pyrrolopyridine, furopyridine, indole,benzofuran, benzothiofuran, benzindole, benzoxazole, pyrroloquinoline,and the like. Unless otherwise noted, polyheteroaryl substituents areunsubstituted or substituted on a carbon atom by one or more suitablesubstituents, including alkyl, the alkyl substituents identified aboveand a substituent of the formula —O—(CH₂CH═CH(CH₃)(CH₂))₁₋₃H. Nitrogenatoms are unsubstituted or substituted, for example by R₁₃; especiallyuseful N substituents include H, C₁-C₄ alkyl, acyl, aminoacyl, andsulfonyl.

[0063] Non-aromatic polyheterocyclic substituents include bicyclic andtricyclic fused ring systems where each ring can be 4-9 membered,contain one or more heteroatom, for example, 1, 2, 3, or 4 heteroatoms,chosen from O, N or S and contain zero or one or more C—C double ortriple bonds. Suitable examples of non-aromatic polyheterocycles includehexitol, cis-perhydrocyclohepta[b]pyridinyl,decahydro-benzo[f][1,4]oxazepinyl, 2,8-dioxabicyclo[3.3.0]octane,hexahydro-thieno[3,2-b]thiophene, perhydropyrrolo[3,2-b]pyrrole,perhydronaphthyridine, perhydro-1H-dicyclopenta[b,e]pyran. Unlessotherwise noted, non-aromatic polyheterocyclic substituents areunsubstituted or substituted on a carbon atom by one or moresubstituents, including alkyl and the alkyl substituents identifiedabove. Nitrogen atoms are unsubstituted or substituted, for example, byR₁₃; especially useful N substituents include H, C₁-C₄ alkyl, acyl,aminoacyl, and sulfonyl.

[0064] Mixed aryl and non-aryl polyheterocycles substituents includebicyclic and tricyclic fused ring systems where each ring can be 4-9membered, contain one or more heteroatom chosen from O, N or S, and atleast one of the rings must be aromatic. Suitable examples of mixed aryland non-aryl polyheterocycles include 2,3-dihydroindole,1,2,3,4-tetrahydroquinoline, 5,11-dihydro-10H-dibenz[b,e][1,4]diazepine,5H-dibenzo[b,e][1,4]diazepine,1,2-dihydropyrrolo[3,4-b][1,5]benzodiazepine,1,5-dihydro-pyrido[2,3-b][1,4]diazepin-4-one,1,2,3,4,6,11-hexahydrobenzo[b]pyrido[2,3-e][1,4]diazepin-5-one. Unlessotherwise noted, mixed aryl and non-aryl polyheterocyclic substituentsare unsubstituted or substituted on a carbon atom by one or moresuitable substituents, including, —N—OH, ═N—OH, alkyl and the alkylsubstituents identified above. Nitrogen atoms are unsubstituted orsubstituted, for example, by R₁₃; especially useful N substituentsinclude H, C₁-C₄ alkyl, acyl, aminoacyl, and sulfonyl.

[0065] Amino substituents include primary, secondary and tertiary aminesand in salt form, quaternary amines. Examples of amino substituentsinclude mono- and di-alkylamino, mono- and di-aryl amino, mono- anddi-arylalkyl amino, aryl-arylalkylamino, alkyl-arylamino,alkyl-arylalkylamino and the like.

[0066] Sulfonyl substituents include alkylsulfonyl and arylsulfonyl, forexample methane sulfonyl, benzene sulfonyl, tosyl and the like.

[0067] Acyl substituents include groups of formula —C(O)—W, —C(O)—W,—C(O)—O—W or —C(O)NR₁₃R₁₄, where W is R₁₆, H or cycloalkylalkyl.

[0068] Acylamino substituents include substituents of the formula—N(R₁₂)C(O)—W, —N(R₁₂)C(O)—O—W, and —N(R₁₂)C(O)—NHOH and R₁₂ and W aredefined above.

[0069] The R₂ substituent HON—C(O)—CH═C(R₁)-aryl-alkyl- is a group ofthe formula

[0070] Preferences for each of the substituents include the following:

[0071] R₁ is H, halo, or a straight chain C₁-C₄ alkyl;

[0072] R₂ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉heterocycloalkyl, alkylcycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, —(CH₂)_(n)C(O)R₆, amino acyl, and —(CH₂)_(n)R₇;

[0073] R₃ and R₄ are the same or different and independently selectedfrom H, and C₁-C₆ alkyl, or R₃ and R₄ together with the carbon to whichthey are bound represent C═O, C═S, or C═NR₈;

[0074] R₅ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, aaromatic polycycle, a non-aromatic polycycle, a mixed aryl and non-arylpolycycle, polyheteroaryl, a non-aromatic polyheterocycle, and a mixedaryl and non-aryl polyheterocycle;

[0075] n, n₁, n₂ and n₃ are the same or different and independentlyselected from 0-6, when n₁ is 1-6, each carbon atom is unsubstituted orindependently substituted with R₃ and/or R₄;

[0076] X and Y are the same or different and independently selected fromH, halo, C₁-C₄ alkyl, CF₃, NO₂, C(O)R₁, OR₉, SR₉, CN, and NR₁₀R₁₁;

[0077] R₆ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉heterocycloalkyl, alkylcycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, OR₁₂, and NR₁₃R₁₄;

[0078] R₇ is selected from OR₁₅, SR₁₅, S(O)R₁₆, SO₂R₁₇, NR₁₃R₁₄, andNR₁₂SO₂R₆;

[0079] R₈ is selected from H, OR₁₅, NR₁₃R₁₄, C₁-C₆ alkyl, C₄-C₉cycloalkyl, C₄-C₉ heterocycloalkyl, aryl, heteroaryl, arylalkyl, andheteroarylalkyl;

[0080] R₉ is selected from C₁-C₄ alkyl and C(O)-alkyl;

[0081] R₁₀ and R₁₁ are the same or different and independently selectedfrom H, C₁-C₄ alkyl, and —C(O)-alkyl;

[0082] R₁₂ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉heterocycloalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl;

[0083] R₁₃ and R₁₄ are the same or different and independently selectedfrom H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl, aryl,heteroaryl, arylalkyl, heteroarylalkyl and amino acyl;

[0084] R₁₅ is selected from H, C₁-C₆ alkyl, C₄ -C₉ cycloalkyl, C₄-C₉heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and(CH₂)_(m)ZR₁₂;

[0085] R₁₆ is selected from C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and(CH₂)_(m)ZR₁₂;

[0086] R₁₇ is selected from C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl andNR₁₃R₁₄;

[0087] m is an integer selected from 0 to 6; and

[0088] Z is selected from O, NR₁₃, S, S(O),

[0089] or a pharmaceutically acceptable salt thereof.

[0090] Useful compounds of the formula (I) include those wherein each ofR₁, X, Y, R₃, and R₄ is H, including those wherein one of n₂ and n₃ iszero and the other is 1, especially those wherein R₂ is H —H or—CH₂—CH₂—OH.

[0091] One suitable genus of hydroxamate compounds are those of formulaIa:

[0092] wherein

[0093] n₄ is 0-3,

[0094] R₂ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉heterocycloalkyl, alkylcycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, —(CH₂)_(n)C(O)R₆, amino acyl and —(CH₂)_(n)R₇;

[0095] R₅′ is heteroaryl, heteroarylalkyl (e.g., pyridylmethyl),aromatic polycycles, non-aromatic polycycles, mixed aryl and non-arylpolycycles, polyheteroaryl, or mixed aryl and non-aryl polyheterocycles,

[0096] or a pharmaceutically acceptable salt thereof

[0097] Another suitable genus of hydroxamate compounds are those offormula Ia:

[0098] wherein

[0099] n₄ is 0-3,

[0100] R₂ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉heterocycloalkyl, alkylcycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, —(CH₂)_(n)C(O)R₆, amino acyl and —(CH₂)_(n)R₇;

[0101] R₅′ is aryl, arylalkyl, aromatic polycycles, non-aromaticpolycycles, and mixed aryl and non-aryl polycycles; especially aryl,such as p-fluorophenyl, p-chlorophenyl, p-O—C₁-C₄-alkylphenyl, such asp-methoxyphenyl, and p-C₁-C₄-alkylphenyl; and arylalkyl, such as benzyl,ortho, meta or para-fluorobenzyl, ortho, meta or para-chlorobenzyl,ortho, meta or para-mono, di or tri-O—C₁-C₄-alkylbenzyl, such as ortho,meta or para-methoxybenzyl, m,p-diethoxybenzyl, o,m,p-triimethoxybenzyl,and ortho, meta or para-mono, di or tri C₁-C₄-alkylphenyl, such asp-methyl, m,m-diethylphenyl,

[0102] or a pharmaceutically acceptable salt thereof.

[0103] Another interesting genus are the compounds of formula Ib:

[0104] wherein

[0105] R₂′ is selected from H, C₁-C₆ alkyl, C₄-C₆ cycloalkyl,cycloalkylalkyl (e.g., cyclopropylmethyl), (CH₂)₂₋₄OR₂₁ where R₂₁ is H,methyl, ethyl, propyl, and 1-propyl, and

[0106] R₅″ is unsubstituted 1H-indol-3-yl, benzofuran-3-yl orquinolin-3-yl, or substituted 1H-indol-3-yl, such as5-fluoro-1H-indol-3-yl or 5-methoxy-1H-indol-3-yl, benzofuran-3-yl orquinolin-3-yl,

[0107] or a pharmaceutically acceptable salt thereof.

[0108] Another interesting genus of hydroxamate compounds are thecompounds of formula (Ic)

[0109] wherein

[0110] the ring containing Z₁ is aromatic or non-aromatic, whichnon-aromatic rings are saturated or unsaturated,

[0111] Z₁ is 0, S or N—R₂₀,

[0112] R₁₈ is H, halo, C₁-C₆alkyl (methyl, ethyl, t-butyl),C₃-C₇cycloalkyl, aryl, for example unsubstituted phenyl or phenylsubstituted by 4-OCH₃ or 4—CF₃, or heteroaryl, such as 2-furanyl,2-thiophenyl or 2-, 3- or 4-pyridyl;

[0113] R₂₀ is H, C₁-C₆alkyl, C₁-C₆alkyl-C₃-C₉cycloalkyl (e.g.,cyclopropylmethyl), aryl, heteroaryl, arylalkyl (e.g., benzyl),heteroarylalkyl (e.g., pyridylmethyl), acyl (acetyl, propionyl, benzoyl)or sulfonyl (methanesulfonyl, ethanesulfonyl, benzenesulfonyl,toluenesulfonyl)

[0114] A₁ is 1, 2 or 3 substituents which are independently H,C₁-C₆alkyl, —OR₁g, halo, alkylamino, aminoalkyl, halo, orheteroarylalkyl (e.g., pyridylmethyl),

[0115] R₁₉ is selected from H, C₁-C₆alkyl, C₄-C₉cycloalkyl,C₄-C₉heterocycloalkyl, aryl, heteroaryl, arylalkyl (e.g., benzyl),heteroarylalkyl (e.g., pyridylmethyl) and —(CH₂CH═CH(CH₃)(CH₂))₁₋₃H;

[0116] R₂ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉heterocycloalkyl, alkylcycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, —(CH₂)_(n)C(O)R₆, amino acyl and —(CH₂)_(n)R₇;

[0117] v is 0, 1 or 2,

[0118] p is 0-3, and

[0119] q is 1-5 and r is 0 or

[0120] q is 0 and r is 1-5,

[0121] or a pharmaceutically acceptable salt thereof. The other variablesubstituents are as defined above.

[0122] Especially useful compounds of formula (Ic) are those wherein R₂is H, or —(CH₂)_(p)CH₂OH, wherein p is 1-3, especially those wherein R₁is H; such as those wherein R₁ is H and X and Y are each H, and whereinq is 1-3 and r is 0 or wherein q is 0 and r is 1-3, especially thosewherein Z. is N—R₂₀. Among these compounds R₂ is preferably H or—CH₂—CH₂—OH and the sum of q and r is preferably 1.

[0123] Another interesting genus of hydroxamate compounds are thecompounds of formula (Id)

[0124] wherein

[0125] Z₁ is O, S or N—R₂₀,

[0126] R₁₈ is H, halo, C₁-C₆alkyl (methyl, ethyl, t-butyl),C₃-C₇cycloalkyl, aryl, for example, unsubstituted phenyl or phenylsubstituted by 4-OCH₃ or 4—CF₃, or heteroaryl,

[0127] R₂₀ is H, C₁-C₆alkyl, C₁-C₆alkyl-C₃-C₉cycloalkyl (e.g.,cyclopropylmethyl), aryl, heteroaryl, arylalkyl (e.g., benzyl),heteroarylalkyl (e.g., pyridylmethyl), acyl (acetyl, propionyl, benzoyl)or sulfonyl (methanesulfonyl, ethanesulfonyl, benzenesulfonyl,toluenesulfonyl),

[0128] A₁ is 1, 2 or 3 substituents which are independently H,C₁-C₆alkyl, —OR₁₉, or halo,

[0129] R₁₉ is selected from H, C₁-C₆alkyl, C₄-C₉cycloalkyl,C₄-C₉heterocycloalkyl, aryl, heteroaryl, arylalkyl (e.g., benzyl), andheteroarylalkyl (e.g., pyridylmethyl);

[0130] p is 0-3, and

[0131] q is 1-5 and r is 0 or

[0132] q is 0 and r is 1-5,

[0133] or a pharmaceutically acceptable salt thereof. The other variablesubstituents are as defined above.

[0134] Especially useful compounds of formula (Id) are those wherein R₂is H, or —(CH₂)_(p)CH₂OH, wherein p is 1-3, especially those wherein RIis H; such as those wherein R₁ is H and X and Y are each H, and whereinq is 1-3 and r is 0 or wherein q is 0 and r is 1-3. Among thesecompounds R₂ is preferably H or —CH₂—CH₂—OH and the sum of q and r ispreferably 1.

[0135] The present invention further relates to compounds of the formula(Ie)

[0136] or a pharmaceutically acceptable salt thereof. The variablesubstituents are as defined above.

[0137] Especially useful compounds of formula (Ie) are those wherein R₁₈is H, fluoro, chloro, bromo, a C₁-C₄alkyl group, a substitutedC₁-C₄alkyl group, a C₃-C₇cycloalkyl group, unsubstituted phenyl, phenylsubstituted in the para position, or a heteroaryl (e.g., pyridyl) ring.

[0138] Another group of useful compounds of formula (Ie) are thosewherein R₂ is H, or —(CH₂)_(p)CH₂OH, wherein p is 1-3, especially thosewherein R₁ is H; such as those wherein R₁ is H and X and Y are each H,and wherein q is 1-3 and r is 0 or wherein q is 0 and r is 1-3. Amongthese compounds R₂ is preferably H or —CH₂—CH₂—OH and the sum of q and ris preferably 1.

[0139] Another group of useful compounds of formula (Ie) are thosewherein R18 is H, methyl, ethyl, t-butyl, trifluoromethyl, cyclohexyl,phenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 2-furanyl,2-thiophenyl, or 2-, 3- or 4-pyridyl wherein the 2-furanyl, 2-thiophenyland 2-, 3- or 4-pyridyl substituents are unsubstituted or substituted asdescribed above for heteroaryl rings; R₂ is H, or —(CH₂)_(p)CH₂OH,wherein p is 1-3; especially those wherein R₁ is H and X and Y are eachH, and wherein q is 1-3 and r is 0 or wherein q is 0 and r is 1-3. Amongthese compounds R₂ is preferably H or —CH₂—CH₂—OH and the sum of q and ris preferably 1.

[0140] Those compounds of formula le wherein R₂₀ is H or C₁-C₆alkyl,especially H, are important members of each of the subgenuses ofcompounds of formula le described above.N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,N-hydroxy-3-[4-[[[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamideandN-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof, are important compoundsof formula (Ie).

[0141] The present invention further relates to the compounds of theformula (If):

[0142] or a pharmaceutically acceptable salt thereof. The variablesubstituents are as defined above.

[0143] Useful compounds of formula (If) are include those wherein R₂ isH, or —(CH₂)_(p)CH₂OH, wherein p is 1-3, especially those wherein R₁ isH; such as those wherein R₁ is H and X and Y are each H, and wherein qis 1-3 and r is 0 or wherein q is 0 and r is 1-3. Among these compoundsR₂ is preferably H or —CH₂—CH₂—OH and the sum of q and r is preferably1.

[0144]N-hydroxy-3-[4-[[[2-(benzofur-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamidesor a pharmaceutically acceptable salt thereof, is an important compoundof formula (If).

[0145] The compounds described above are often used in the form of apharmaceutically acceptable salt. Pharmaceutically acceptable saltsinclude, when appropriate, pharmaceutically acceptable base additionsalts and acid addition salts, for example, metal salts, such as alkaliand alkaline earth metal salts, ammonium salts, organic amine additionsalts, and amino acid addition salts, and sulfonate salts. Acid additionsalts include inorganic acid addition salts such as hydrochloride,sulfate and phosphate, and organic acid addition salts such as alkylsulfonate, arylsulfonate, acetate, maleate, fumarate, tartrate, citrateand lactate. Examples of metal salts are alkali metal salts, such aslithium salt, sodium salt and potassium salt, alkaline earth metal saltssuch as magnesium salt and calcium salt, aluminum salt, and zinc salt.Examples of ammonium salts are ammonium salt and tetramethylammoniumsalt. Examples of organic amine addition salts are salts with morpholineand piperidine. Examples of amino acid addition salts are salts withglycine, phenylalanine, glutamic acid and lysine. Sulfonate saltsinclude mesylate, tosylate and benzene sulfonic acid salts.

[0146] As is evident to those skilled in the art, the many of thedeacetylase inhibitor compounds of the present invention containasymmetric carbon atoms. It should be understood, therefore, that theindividual stereoisomers are contemplated as being included within thescope of this invention.

[0147] The hydroxamate compounds of the present invention can beproduced by known organic synthesis methods. For example, thehydroxamate compounds can be produced by reacting methyl 4-formylcinnamate with tryptamine and then converting the reactant to thehydroxamate compounds. As an example, methyl 4-formyl cinnamate 2, isprepared by acid catalyzed esterification of 4-formylcinnamic acid 3(Bull. Chem. Soc. Jpn. 1995; 68:2355-2362). An alternate preparation ofmethyl 4-formyl cinnamate 2 is by a Pd-catalyzed coupling of methylacrylate 4 with 4-bromobenzaldehyde 5.

[0148] Additional starting materials can be prepared from4-carboxybenzaldehyde 6, and an exemplary method is illustrated for thepreparation of aldehyde 9, shown below. The carboxylic acid in4-carboxybenzaldehyde 6 can be protected as a silyl ester (e.g., thet-butyldimethylsilyl ester) by treatment with a silyl chloride (e.g.,t-butyldimethylsilyl chloride) and a base (e.g. triethylamine) in anappropriate solvent (e.g., dichloromethane). The resulting silyl ester 7can undergo an olefination reaction (e.g., a Homer-Emmons olefination)with a phosphonate ester (e.g., triethyl 2-phosphonopropionate) in thepresence of a base (e.g., sodium hydride) in an appropriate solvent(e.g., tetrahydrofuran (THF)). Treatment of the resulting diester withacid (e.g., aqueous hydrochloric acid) results in the hydrolysis of thesilyl ester providing acid 8. Selective reduction of the carboxylic acidof 8 using, for example, borane-dimethylsuflide complex in a solvent(e.g., THF) provides an intermediate alcohol. This intermediate alcoholcould be oxidized to aldehyde 9 by a number of known methods, including,but not limited to, Swern oxidation, Dess-Martin periodinane oxidation,Moffatt oxidation and the like.

[0149] The aldehyde starting materials 2 or 9 can be reductivelyaminated to provide secondary or tertiary amines. This is illustrated bythe reaction of methyl 4-formyl cinnamate 2 with tryptamine 10 usingsodium triacetoxyborohydride (NaBH(OAc)₃) as the reducing agent indichloroethane (DCE) as solvent to provide amine 11. Other reducingagents can be used, e.g., sodium borohydride (NaBH₄) and sodiumcyanoborohydride (NaBH₃CN), in other solvents or solvent mixtures in thepresence or absence of acid catatylysts (e.g., acetic acid andtrifluoroacetic acid). Amine 11 can be converted directly to hydroxamicacid 12 by treatment with 50% aqueous hydroxylamine in a suitablesolvent (e.g., THF in the presence of a base, e.g., NaOH). Other methodsof hydroxamate formation are known and include reaction of an ester withhydroxylamine hydrochloride and a base (e.g., sodium hydroxide or sodiummethoxide) in a suitable solvent or solvent mixture (e.g., methanol,ethanol or methanol/THF).

[0150] Aldehyde 2 can be reductively aminated with a variety of amines,exemplified by, but not limited to, those illustrated in Table 1. Theresulting esters can be converted to target hydroxamates by the methodslisted. TABLE 1

Amine Reducing Conditions Hydroxamate Conditions R

NaBH(OAc)₃HOAc, DCE 2 M HONH₂ in MeOH

″ ″

″ ″

″ ″

″ ″

″ ″

″ ″

″ ″

″ ″

Ph(CH₂)₃NH₂ NaBH₃CN/MeOH/HOAc Ph(CH₂)₃

[0151] An alternate synthesis of the compounds of this invention startsby reductive amination of 4-formyl cinnamic acid 3, illustrated belowwith 3-phenylpropylamine 13, using, for example, NaBH₃CN as the reducingagent in MeOH and HOAc as a catalyst. The basic nitrogen of theresulting amino acid 14 can be protected, for example, ast-butoxycarbamate (BOC) by reaction with di-t-butyldicarbonate to give15.

[0152] The carboxylic acid can be coupled with a protected hydroxylamine(e.g., O-trityl hydroxylamine) using a dehydrating agent (e.g.,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI)) anda catalyst (e.g., 1-hydroxybenzotriazole hydrate (HOBT)) in a suitablesolvent (e.g., DMF) to produce 16. Treatment of 16 with a strong acid(e.g., trifluoroacetic acid (TFA)) provides a hydroxamic acid 17 of thepresent invention. Additional examples of compounds that can be preparedby this method are:

[0153] Tertiary amine compounds can be prepared by a number of methods.Reductive amination of 30 with nicotinaldehyde 32 using NaBH₃CN as thereducing agent in dichloroethane and HOAc as a catalyst provides ester34. Other reducing agents can be used (e.g., NaBH₄ and NaBH(OAc)₃ ) inother solvents or solvent mixtures in the presence or absence of acidcatalysts (e.g., acetic acid, trifluoroacetic acid and the like).Reaction of ester 34 with HONH₂.HCl, NaOH in MeOH provides hydroxamate36.

[0154] Tertiary amine compounds prepared by this methodology areexemplified, but not limited to, those listed in Table 2.Table 2

or

Reducing Hydroxamate Conditions Conditions

NaBH(OAc)₃HOAc, DCE HONH₂.HCl/NaOMe/ MeOH

NaBH(OAc)₃HOAc, DCE HONH₂.HCl/NaOMe/ MeOH

NaBH(OAc)₃HOAc, DCE 2 M HONH₂ in MeOH

NaBH₃CN/MeOH/ HOAc 2 M HONH₂ in MeOH

NaBH(OAc)₃HOAc, DCE 2 M HONH₂ in MeOH

[0155] An alternate method for preparing tertiary amines is by reactinga secondary amine with an alkylating agent in a suitable solvent in thepresence of a base. For example, heating a dimethylsulfoxide (DMSO)solution of amine 11 and bromide 40 in the presence of (i-Pr)₂NEtyielded tertiary amine 42. Reaction of the tertiary amine 42 withHONH₂.HCl, NaOH in MeOH provides hydroxamate 43. The silyl group can beremoved by any method known to those skilled in the art. For example,the hydroxamate 43 can be treated with an acid, e.g., trifluoroaceticacid, or fluoride to produce hydroxyethyl compound 44.

[0156] The hydroxamate compound, or salt thereof, is suitable forpreparing pharmaceutical compositions, especially pharmaceuticalcompositions having deacetylase, especially histone deacetylase,inhibiting properties. Studies with athymic mice demonstrate that thehydroxamate compound causes HDA inhibition and increased histoneacetylation in vivo, which triggers changes in gene expression thatcorrelate with tumor growth inhibition.

[0157] The present invention further includes pharmaceuticalcompositions comprising a pharmaceutically effective amount of one ormore of the above-described compounds as active ingredient.Pharmaceutical compositions according to the invention are suitable forenteral, such as oral or rectal, and parenteral administration tomammals, including man, for the treatment of tumors, alone or incombination with one or more pharmaceutically acceptable carriers.

[0158] The hydroxamate compound is useful in the manufacture ofpharmaceutical compositions having an effective amount the compound inconjunction or admixture with excipients or carriers suitable for eitherenteral or parenteral application. Preferred are tablets and gelatincapsules comprising the active ingredient together with (a) diluents;(b) lubricants, (c) binders (tablets); if desired, (d) disintegrants;and/or (e) absorbents, colorants, flavors and sweeteners. Injectablecompositions are preferably aqueous isotonic solutions or suspensions,and suppositories are advantageously prepared from fatty emulsions orsuspensions. The compositions may be sterilized and/or containadjuvants, such as preserving, stabilizing, wetting or emulsifyingagents, solution promoters, salts for regulating the osmotic pressureand/or buffers. In addition, the compositions may also contain othertherapeutically valuable substances. The compositions are preparedaccording to conventional mixing, granulating or coating methods,respectively, and contain preferably about 1 to 50% of the activeingredient.

[0159] Suitable formulations also include formulations for parenteraladministration include aqueous and non-aqueous sterile injectionsolutions which may contain antioxidants, buffers, bacteriostats andsolutes which render the formulation isotonic with the blood of theintended recipient; and aqueous and non-aqueous sterile suspensionswhich may include suspending agents and thickening agents. Theformulations may be presented in unit-dose or multi-dose containers, forexample, sealed ampules and vials, and may be stored in a freeze-dried(lyophilized) condition requiring only the addition of the sterileliquid carrier, for example, water for injections, immediately prior touse. Extemporaneous injection solutions and suspensions may be preparedfrom sterile powders, granules and tablets of the kind previouslydescribed.

[0160] As discussed above, the compounds of the present invention areuseful for treating proliferative diseases. A proliferative disease ismainly a tumor disease (or cancer) (and/or any metastases). Theinventive compounds are particularly useful for treating a tumor whichis a breast cancer, genitourinary cancer, lung cancer, gastrointestinalcancer, epidermoid cancer, melanoma, ovarian cancer, pancreas cancer,neuroblastoma, head and/or neck cancer or bladder cancer, or in abroader sense renal, brain or gastric cancer; in particular (i) a breasttumor; an epidermoid tumor, such as an epidermoid head and/or neck tumoror a mouth tumor; a lung tumor, for example a small cell or non-smallcell lung tumor; a gastrointestinal tumor, for example, a colorectaltumor; or a genitourinary tumor, for example, a prostate tumor(especially a hormone-refractory prostate tumor); or (ii) aproliferative disease that is refractory to the treatment with otherchemotherapeutics; or (iii) a tumor that is refractory to treatment withother chemotherapeutics due to multidrug resistance.

[0161] In a broader sense of the invention, a proliferative disease mayfurthermore be a hyperproliferative condition such as leukemias,hyperplasias, fibrosis (especially pulmonary, but also other types offibrosis, such as renal fibrosis), angiogenesis, psoriasis,atherosclerosis and smooth muscle proliferation in the blood vessels,such as stenosis or restenosis following angioplasty.

[0162] Where a tumor, a tumor disease, a carcinoma or a cancer arementioned, also metastasis in the original organ or tissue and/or in anyother location are implied alternatively or in addition, whatever thelocation of the tumor and/or metastasis.

[0163] The compound is selectively toxic or more toxic to rapidlypropiferating cells than to normal cells, particularly in human cancercells, e.g., cancerous tumors, the compound has significantantiproliferative effects and promotes differentiation, e.g., cell cyclearrest and apoptosis. In addition, the hydroxamate compound induces p21,cyclin-CDK interacting protein, which induces either apoptosis or G1arrest in a variety of cell lines.

[0164] The following examples are intended to illustrate the inventionand are not to be construed as being limitations thereto.

EXAMPLE P1

[0165] Preparation ofN-Hydroxy-3-[4-[[[2-(1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide.

[0166] 4-formylcinnamic acid methylester is produced by adding4-formylcinnamic acid (25 g, 0.143 mol) in MeOH and HCl (6.7 g, 0.18mol). The resulting suspension is heated to reflux for 3 hours, cooledand evaporated to dryness. The resulting yellow solid is dissolved inEtOAc, the solution washed with saturated NaHCO₃, dried (MgSO₄) andevaporated to give a pale yellow solid which is used without furtherpurification (25.0 g, 92%). To a solution of tryptamine (16.3 g, 100mmol) and 4-formylcinnamic acid methylester (19 g, 100 mmol) indichloroethane, NaBH(OAc)₃ (21 g, 100 mmol) is added. After 4 hours themixture is diluted with 10% K₂CO₃ solution, the organic phase separatedand the aqueous solution extracted with CH₂Cl₂. The combined organicextracts are dried (Na₂SO₄), evaporated and the residue purified byflash chromatography to produce3-(4-{[2-(1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-(2E)-2-propenoicacid methyl ester (29 g). A solution of KOH (12.9 g 87%, 0.2 mol) inMeOH (100 mL) is added to a solution of HONH₂-HCl (13.9 g, 0.2 mol) inMeOH (200 mL) and a precipitate results. After 15 minutes the mixture isfiltered, the filter cake washed with MeOH and the filtrate evaporatedunder vacuum to approximately 75 mL. The mixture is filtered and thevolume adjusted to 100 mL with MeOH. The resulting solution 2M HONH₂ isstored under N₂ at −20° C. for up to 2 weeks. Then3-(4-{[2-(1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-(2E)-2-propenoicacid methyl ester (2.20 g, 6.50 mmol) is added to 2 M HONH₂ in MeOH (30mL, 60 mmol) followed by a solution of KOH (420 mg, 6.5 mmol) in MeOH (5mL). After 2 hours dry ice is added to the reaction and the mixture isevaporated to dryness. The residue is dissolved in hot MeOH (20 mL),cooled and stored at −20° C. overnight. The resulting suspension isfiltered, the solids washed with ice cold MeOH and dried under vacuum,producingN-Hydroxy-3-[4-[[[2-(1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide(m/z 336 [MH⁺]).

EXAMPLE P2

[0167] Preparation ofN-Hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide

[0168] A solution of3-(4-{[2-(1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-(2E)-2-propenoicacid methyl ester (12.6 g, 37.7 mmol),(2-bromoethoxy)-tert-butyldimethylsilane (12.8 g, 53.6 mmol),(i-Pr)₂NEt, (7.42 g, 57.4 mmol) in DMSO (100 mL) is heated to 50° C.After 8 hours the mixture is partitioned with CH₂Cl₂/H₂O. The organiclayer is dried (Na₂SO₄) and evaporated. The residue is chromatographedon silica gel to produce3-[4-({[2-(tert-butyidimethylsilanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-phenyl]-(2E)-2-propenoicacid methyl ester (13.1 g). Following the procedure described for thepreparation of the hydroxamate compound in ExampleP1,3-[4-({[2-(tert-butyidimethylsilanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-phenyl]-(2E)-2-propenoicacid methyl ester (5.4 g, 11 mmol) is converted toN-hydroxy-3-[4-({[2-(tert-butyldimethylsilanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-phenyl]-(2E)-2-propenamide(5.1 g,) and used without further purification. The hydroxamic acid (5.0g, 13.3 mmol) is then dissolved in 95% TFA/H₂O (59 mL) and heated to40-50° C. for 4 hours. The mixture is evaporated and the residuepurified by reverse phase HPLC to produceN-Hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamideas the trifluoroacetate salt (m/z 380 [MH⁺]).

EXAMPLE P3

[0169] Preparation ofN-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide.

[0170] A suspension of LiAlH₄ (17 g, 445 mmol) in dry THF (1000 mL) iscooled to 0° C. and 2-methylindole-3-glyoxylamide (30 g, 148 mmol) isadded in portions over 30 min. The mixture is stirred at roomtemperature for 30 min. and then maintained at reflux for 3 h. Thereaction is cooled to 0° C. and treated with H₂O (17 ml), 15% NaOH (aq.,17ml) and H₂O (51 ml). The mixture is treated with MgSO₄, filtered andthe filtrate evaporated to give 2-methyltryptamine which is dissolved inMeOH. Methyl 4-formylcinnamate (16.9 g, 88.8 mmol) is added to thesolution, followed by NaBH₃CN (8.4 g) and AcOH (1 equiv.). After 1 h thereaction is diluted with NaHCO₃ (aq.) and extracted with EtOAc. Theorganic extracts are dried (MgSO₄), filtered and evaporated. The residueis purified by chromatography to give3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-(2E)-2-propenoicacid methyl ester. The ester is dissolved in MeOH, 1.0 M HCl/dioxane(1-1.5 eqiv.) is added followed by Et₂O. The resulting precipitate isfiltered and the solid washed with Et₂O and dried thoroughly to give3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-(2E)-2-propenoicacid methyl ester hydrochloride. 1.0 M NaOH (aq., 85 mL) is added to anice cold solution of the methyl ester hydrochloride (14.9 g, 38.6 mmol)and HONH₂ (50% aq. solution, 24.0 5 mL, ca. 391.2 mmol). After 6 h, theice cold solution is diluted with H₂O and NH₄Cl (aq., 0.86 M, 100 mL).The resulting precipitate is filtered, washed with H₂O and dried toaffordN-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide(m/z 350 [MH⁺]).

EXAMPLES 1-265

[0171] The following compounds are prepared by methods analogous tothose disclosed in Examples P1, P2 and P3: Ex- ample STRUCTURE m/z (MH⁺)1

426 2

3

4

325 5

6

7

8

465 9

10

11

12

420 13

420 14

15

465 16

385 17

550 18

432 19

366 20

350 21

22

442 23

338 24

464 25

541 26

27

28

417 29

30

31

380 32

436 33

34

493 35

477 36

586 37

513 38

378 39

408 40

449 41

438 42

452 43

507 44

565 45

46

47

48

49

50

51

470 52

53

548 54

623 55

456 56

478 57

394 58

422 59

479 60

603 61

477 62

539 63

523 64

65

66

67

68

539 69

495 70

71

379 72

478 73

462 74

378 75

76

493 77

503 78

350 79

549 80

471 81

350 82

418 83

486 84

524 85

424 86

364 87

440 88

420 89

390 90

91

92

484 93

498 94

490 95

96

475 97

525 98

422 99

528 100

448 101

437 102

451 103

505 104

519 105

514 106

507 107

626 108

499 109

110

111

429 112

464 113

432 114

422 115

390 116

501 117

484 118

119

587 120

602 121

539 122

123

528 124

487 125

126

556 127

128

129

552 130

519 131

450 132

464 133

558 134

533 135

136

527 137

381 138

364 139

140

448 141

558 142

143

427 144

145

432 146

384 147

354 148

149

150

151

152

153

154

350 155

366 156

408 157

322 158

364 159

364 160

378 161

350 162

463 163

164

381 165

463 166

476 167

168

169

170

368 171

493 172

527 173

515 174

323 175

540 176

441 177

276 178

179

455 180

181

336 182

347 183

447 184

185

420 186

424 187

422 188

189

398 190

418 191

350 192

193

352 194

499 195

408 196

394 197

499 198

199

200

350 201

202

203

204

365 205

465 206

207

410 208

410 209

210

366 211

352 212

213

368 214

338 215

356 216

408 217

368 218

396 219

220

342 221

392 222

412 223

337 224

337 225

456 226

364 227

481 228

355 229

312 230

424 231

232

351 233

392 234

235

236

322 237

238

366 239

240

368 241

242

406 243

398 244

442 245

350 246

364 247

402 248

418 249

364 250

251

408 252

253

254

413 255

405 256

257

394 258

390 259

434 260

386 261

368 262

412 263

406 264

265

378

[0172] The compounds of Examples 1-265 show an HDA enzyme IC₅₀ in therange from about 0.005 to about 0.5 μM.

EXAMPLE B1

[0173] Cell lines H1299 (human lung carcinoma cell) and HCT116 (colontumor cell) are obtained from the American Type Culture Collection,Rockville, Md. The cell lines are free of Mycoplasma contamination(Rapid Detection System by Gen-Probe, Inc., San Diego, Calif.) and viralcontamination (MAP testing by MA BioServices, Inc., Rockville, Md.). Thecell lines are propagated and expanded in RPMI 1640 medium containing10% heat-inactivated FBS (Life Technologies, Grand Island, N.Y.). Cellexpansions for implantation are performed in cell factories (NUNC,purchased from Fisher Scientific, Springfield, N.J.). Cells areharvested at 50-90% confluency, washed once with HBSS (Hank's BalancedSalt Solution) containing 10% FBS, and suspended in 100% HBSS.

[0174] Cell proliferation is measured with a commercial MTS kit(Promega, Madision, Wis.) assay using an adaptation of publishedprocedures, for example, that disclosed in Feasibility of drug screeningwith panels of human tumor cell lines using a microculture tetrazoliumassay, Alley M C, et al., Cancer Res. 1988; 48:589-601. Cells are platedin 96-well tissue culture dishes, with top and bottom rows left empty.H1299 and HCT116 cells are suspended in complete media at a density of5.3×10³ and 3.6×10³ cell/mL, respectively, and 190 μl are added perwell. Each cell line is added to one half of the plate. Complete medium(200 μL) is added to the top and bottom rows. Twenty-four hours later,10 μl of MTS solution is added to one of the plates to determine theactivity at the time of compound addition (T₀). The plate is incubatedat 37° C. for 4 hours and the OD₄₉₀ is measured on a Molecular DevicesThermomax at 490 nm using the Softmax program. The T₀ plate serves as areference for initial activity at the beginning of the experiment.

[0175] Five serial dilutions (1:4) of each compound are made in a96-deep well plate with the highest concentrations on the edge of plate.Two cell lines are tested with two compounds per plate.0 Ten microlitersof each of the five dilutions are added in triplicate and completemedium alone is added to columns six and seven. The plates are incubatedat 37 OC for 72 hours. The MTS solution is added (as for the To plate)and read four hours later.

[0176] In order to analyze the data, the average background value (mediaalone) is subtracted from each experimental well; the triplicate valuesare averaged for each compound dilution. The following formulas are usedto calculate percent growth.

If X>T ₀, % Growth=((X−T ₀)/(GC−T ₀))×100

If X<T ₀, % Growth=(X−T ₀)/T ₀)×100

[0177] in which T₀=(average value of cell viability at time0)−background

[0178] GC=average value of untreated cells (in triplicate)−background

[0179] X=average value of compound treated cells (intriplicate)−background

[0180] The “% Growth” is plotted against compound concentration and usedto calculate IC₅₀s employing the linear regression techniques betweendata points to predict the concentration of compounds at 50% inhibition.

[0181] Lactate salts ofN-hydroxy-3-[4-[[[2-(1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide(CMD1),N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide(CMD2),N-hydroxy-3-[4-[[[2-(5-methoxy-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide(CMD3),N-hydroxy-3-[4-[[[2-(5-fluoro-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide(CMD4),N-hydroxy-3-[4-[[[2-(benzofur-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide(CMD5) having a purity of higher than 95% are dissolved in puredimethylsulfoxide (DMSO) to create a stock solution. The stock solutionis diluted with 5% dextrose injection, USP, just prior to dosing. Inaddition,N-(2-aminophenyl)-4-[N-pyridin-3-yl)methoxycarbonylaminomethyl]benzamideis synthesized in accordance with Example 48 of EP 0 847 992 and used asa control compound (CMDC). Inhibition of cell growth in monolayer for 72hours of compound treatment is measured in triplicate-experiments andused to derive the IC₅₀ by MTS assay. The results are shown in Table B1.TABLE B1 Active Monolayer Growth IC₅₀ (μM) Compound H1299 HCT116 CMD10.40 0.03 CMD2 0.15 0.01 CMD3 0.58 0.03 CMD4 0.28 0.03 CMD5 0.18 0.03CMDC 6.8 0.67

[0182] The results show that the hydroxamate compounds of the presentinvention are highly active in inhibition of tumor cell growth. Inaddition to the above results, it has been observed that the compoundsselectively inhibited tumor cells while showing minimal inhibitionactivities in non-tumorous cells.

[0183] The cells treated with the hydroxamate compounds are also testedfor the induction of p21 promoter, which is a key mediator of G1 arrestand differentiation. The hydroxamate compounds activate the p21 promoterto a readily detectable level at a concentration within two-fold oftheir respective IC₅₀ for monolayer cell growth inhibition in H1299.Without being bound by amy particular theory, the correlation appears todemonstrate that HDA inhibition leads to transcriptional activation ofgenes that inhibit tumor cell proliferation.

EXAMPLE B2

[0184] HDA is partially purified from H1299, human non-small cell lungcarcinoma cells (obtained from American Type Culture Collection, 12301Parklawn Drive, Rockville, Md. 20852, USA). Cells are grown to 70-80%confluence in RPMI media in the presence of 10% FCS, harvested and lysedby sonication. The lysate is centrifuged at 23,420 g for 10-15 min, thesupernatant is applied to a Hiload 26/10High performance Q-sepharosecolumn (Amersham Pharmacia Biotech), and equilibrated with a buffercontaining 20 mM Tris pH8.0, 1 mM EDTA, 10 mM NH₄Cl₂, 1 mMμ-Mercaptoethanol, 5% glycerol, 2 μg/mL aprotinin, 1 μg/mL leupeptin,and 400 mM PMSF. Proteins are eluted in 4mL aliquots with a lineargradient from 0-500 mM NaCl in the above buffer at a flow rate of 2.5mL/min. Each preparation of partially purified HDA enzyme is titrated todetermine the optimal amount needed to obtain a signal to noise ratio ofat least 5 to 1. Generally, 20-30 II of partially purified HDA (5-10 mgprotein/mL) is mixed with 2 μL of compound solution in DMSO in a deepwell titer plate (Beckman). The compounds are serially diluted in DMSOto generate stocks at 20-fold of the assay concentrations. Finalconcentrations of compounds in the assay are 10 μM, 2 μM, 400 nM, 80 nM,and 16 nM with the final percentage of DMSO in each enzyme reactionequaling 0.1%. Each concentration of compound is assayed in duplicate.The substrate used in the reaction is a peptide of amino acid sequence,SGRGKGGKGLGKGGAKRHRKVLRD, corresponding to the twenty-four N-terminalamino acids of human histone H4, biotinylated at the N-terminus andpenta-acetylated, at each lysine residue with ³H-acetate. To initiatethe reaction, the substrate is diluted in 10 μL of Buffer A (100 mM TrispH 8.0, 2 mM EDTA), added to the enzyme mixture and collected at thebottom of the deep well plate by centrifugation for 5 minutes at 1500rpm. Following centrifugation, the mixture is incubated at 37° C. for1.5 hr. The reaction is stopped by the addition of 20 μL of the StopBuffer (0.5N HCl, 0.08M Acetic Acid). At this point, the assay proceedsto the robotic extraction phase or is frozen for several days at −80° C.

[0185] The extraction of enzymatically cleaved ³H-acetate groups fromthe reaction mixture is achieved with the solvent TBME (t-butyl methylether) using the Tomtec Quadra 96 workstation. A program is written toadd 200 μL of TBME to a 96 “deep well” plate. The workstation isprogrammed to aspirate 50 μL of air followed by 200 μL of TBME andfinally another 25 μL of air, which is dispensed into the each well ofthe plate. The contents of the deep well were mixed thoroughly bypipetting 160 μL up and down 10 times. Before addition of TBME to thereaction mixture, it is necessary to “pre-wet” the pipette tips withTBME to prevent the solvent from dripping during the transfer to thedeep well plate. The organic and aqueous phases in the deep well areseparated by centrifugation at 1500 rpm for 5 min. Opti-Phase Supermixliquid scintillation cocktail (200 μL) (Wallac) is added to each well ofthe 96-well Trilux plate (Wallac). The deep well and Trilux plates areplaced back on the workstation programmed to aspirate 25 μL of air intothe pipette tips followed by 100 μL of the upper TBME phase and transferit into the Trilux plate. The solutions are mixed by pipetting andexpelling 50 μL, five times, within the same well. The Trilux plate iscovered with clear film and read on a 1450 MicroBeta Trilux liquidscintillation and luminescence counter (Wallac) with a color/chemicalquench and dpm correction.

[0186] In order to determine the IC₅₀ values, the data are analyzed on aspreadsheet. The analysis requires a correction for the backgroundluminescence that is accomplished by subtracting the dpm values of wellswithout ³H substrate from the experimental wells. The corrected dpmvalues along with the concentrations of the compounds are used tocalculate IC50 using the user-defined spline function. This functionutilizes linear regression techniques between data points to calculatethe concentration of compounds that produced 50% inhibition. The resultsare shown in Table B2. TABLE B2 Compound HDA Enzyme Activity IC₅₀ (μM)CMD1 0.032 CMD2 0.063 CMD3 0.014 CMD4 0.014 CMD5 0.016 CMDC >10

EXAMPLE B3

[0187] The A549 non-small cell lung human tumor cell line is purchasedfrom the American Type Culture Collection, Rockville, Md. The cell lineis free of Mycoplasma contamination (Rapid Detection System byGen-Probe, Inc., San Diego, Calif.) and viral contamination (MAP testingby MA BioServices, Inc., Rockville, Md.). The cell line is propagatedand expanded in RPMI 1640 medium containing 10% heat-inactivated FBS(Life Technologies, Grand Island, N.Y.). Cell expansions forimplantation are performed in cell factories (NUNC, purchased fromFisher Scientific, Springfield, N.J.). Cells are harvested at 50-90%confluency, washed once with HBSS containing 10% FBS, and suspended in100% HBSS.

[0188] Outbred athymic (nu/nu) female mice (“Hsd:Athymic Nude-nu” fromHarlan Sprague Dawley, Indianapolis, Ind.) are anesthetized withMetofane (Mallinckrodt Veterinary, Inc., Mundelein, Ill.), and ˜100 μLof the cell suspension containing 1×10⁷ cells is injected subcutaneouslyinto the right axillary (lateral) region of each animal. Tumors areallowed to grow for about 20 days until a volume of ˜=100 mm³ isachieved. At this point, mice bearing tumors with acceptable morphologyand size are sorted into groups of eight for the study. The sortingprocess produces groups balanced with respect to mean and range of tumorsize. Antitumor activity is expressed as % T/C, comparing differences intumor volumes for treatment group (T) to vehicle control group (C).Regressions are calculated using the formula: (1-T/T₀)×100%, where T isthe tumor volume for the treatment group at the end of the experiment,and T₀ is the tumor volume at the beginning of the experiment.

[0189] CMD1 is administered intravenously, once daily 5×/week for threeweeks, at doses of 10, 25, 50, or 100 mg/kg. The final DMSOconcentration is 10%. Each test group has eight mice. Tumors aremeasured, and individual animal body weights recorded. Table B3 showsthe results on the 41^(st) day. TABLE B3 Δ MEAN Δ % TUMOR BODY DOSEVOLUME*¹ WEIGHT*² COMPOUND (mg/kg) (mm³ ± SEM*³) % T/C (% ± SEM*³) 10%DMSO/ — 376 ± 55 — +11.9 ± 0.2  D5W*⁴ CMD1 10 121 ± 27 32 +1.3 ± 0.3CMD1 25  77 ± 32 20 −0.9 ± 0.3 CMD1 50  57 ± 10 15 −0.4 ± 0.3 CMD1 100  28 ± 25  7 +0.4 ± 0.3

EXAMPLE B4

[0190] Example B3 repeated except CMD2 is used. Table B4 shows theresults. TABLE B4 Δ MEAN Δ % TUMOR BODY DOSE VOLUME WEIGHT COMPOUND(mg/kg) (mm³ ± SEM) % T/C (% ± SEM) 10% DMSO/ — 135 ± 43 — +6.7 ± 1.1D5W CMD2 25  37 ± 16 27 −4.2 ± 2.5 CMD2 50  29 ± 15 21 −2.9 ± 1.5

EXAMPLE B5

[0191] Example B3 is repeated except the HCT116 colon tumor cell line isused in place of the A549 cell line. The HCT116 cell line is alsoobtained from American Type Culture Collection, Rockville, Md., and thecell line is free of Mycoplasma contamination and viral contamination.The results are recorded on the 34^(th) day and are shown in Table B5.TABLE B5 Δ MEAN Δ % TUMOR BODY DOSE VOLUME* WEIGHT COMPOUND (mg/kg) (mm³± SEM) % T/C (% ± SEM) 10% DMSO/ — 759 ± 108 — −0.4 ± 0.4 D5W CMD1 50*¹⁰ 186 ± 40  25 −7.4 ± 0.8 CMD1 100 140 ± 38  18 −3.2 ± 0.4

EXAMPLE B6

[0192] Example B4 is repeated except the HCT116 colon tumor cell line isused in place of the A549 cell line. The HCT116 is also obtained fromAmerican Type Culture Collection, Rockville, Md., and the cell line isfree of Mycoplasma contamination and viral contamination. The resultsare recorded on the ₃₄th day and are shown in Table B6. TABLE B6 Δ MEANTUMOR Δ % BODY DOSE VOLUME WEIGHT COMPOUND (mg/kg) (mm³ ± SEM) % T/C (%± SEM) 10% DMSO/ —  759 ± 108 — −0.4 ± 0.4 D5W CMD2 10 422 ± 75 56 −10.2± 0.5  CMD2 25 305 ± 47 40 −7.0 ± 0.2 CMD2 50  97 ± 30 13 −7.3 ± 0.3CMD2 100  132 ± 30 17 −9.4 ± 0.4

EXAMPLE B7

[0193] Annexin V binding was used as a marker for the early stages ofapoptosis. A549,HCT116 and Normal Dermal Human Fibroblasts (NDHF) cellsare treated separately with four compounds (CMD1, CMD2, CMD3 and CMD4)for 24 or 48 hours, stained with annexin V and compared to cells treatedsimilarly with vehicle (DMSO). Cells are examined by fluorescencemicroscopy. Those undergoing apoptosis exhibit green fluorescentmembrane staining. Viability is assessed by the counterstain, propidiumiodide. Cells detected by red fluorescence are not viable. A smallpercentage of A549 and the majority of HCT116 cells exhibit cell surfacestaining with annexin V after 24 hour exposure to each of the fourcompounds. After 48 hour treatment, the majority of the A549 and HCT116stain with annexin V and/or propidium iodide indicating that thecompounds induce apoptotic cell death. In contrast, NDHF cells do notshow noticeable annexin V staining after 24 hour exposure and limitedannexin V staining with CMD3 after 48 hour. These data show that NDHFcells predominantly underwent non-lethal growth arrest upon compoundtreatment, consistent with the cell cycle profile.

[0194] The staining results demonstrate that the hydroxamate compoundsof the present invention cause tumor cells to die by apoptosis, whilecausing normal fibroblast to predominantly undergo cell cycle arrest,clearly demonstrating the selective efficacy of the present compounds.

What is claimed is:
 1. A compound of the formula (I)

wherein R₁ is H, halo, or a straight chain C₁-C₆ alkyl; R₂ is selectedfrom H, C₁-C₁₀ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl, C₄-C₉heterocycloalkylalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, —(CH₂)_(n)C(O)R₆, —(CH₂)_(n)OC(O)R₆, amino acyl,HON—C(O)—CH═C(R₁)-aryl-alkyl- and —(CH₂)_(n)R₇; R₃ and R₄ are the sameor different and independently H, C₁-C₆ alkyl, acyl or acylamino, or R₃and R₄ together with the carbon to which they are bound represent C═O,C═S, or C═NR₈, or R₂ together with the nitrogen to which it is bound andR₃ together with the carbon to which it is bound can form a C₄-C₉heterocycloalkyl, a heteroaryl, a polyheteroaryl, a non-aromaticpolyheterocycle, or a mixed aryl and non-aryl polyheterocycle ring; R₅is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉heterocycloalkyl, acyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,aromatic polycycle, non-aromatic polycycle, mixed aryl and non-arylpolycycle, polyheteroaryl, non-aromatic polyheterocycle, and mixed aryland non-aryl polyheterocycle; n, n₁, n₂ and n₃ are the same or differentand independently selected from 0-6, when n, is 1-6, each carbon atomcan be optionally and independently substituted with R₃ and/or R₄; X andY are the same or different and independently selected from H, halo,C₁-C₄ alkyl, NO₂, C(O)R₁, OR₉, SR₉, ON, and NR₁₀R₁₁; R₆ is selected fromH, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl,cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, OR₁₂, andNR₁₃R₁₄; R₇ is selected from OR₁₅, SR₁₅, S(O)R₁₆, SO₂R₁₇, NR₁₃R₁₄, andNR₁₂SO₂R₆; R₈ is selected from H, R₁₅, NR₁₃R₁₄, C₁-C₆ alkyl, C₄-C₉cycloalkyl, C₄-C₉ heterocycloalkyl, aryl, heteroaryl, arylalkyl, andheteroarylalkyl; R₉ is selected from C₁-C₄ alkyl and C(O)-alkyl; R₁₀ andR₁₁ are the same or different and independently selected from H, C₁-C₄alkyl, and —C(O)-alkyl; R₁₂ is selected from H, C₁-C₆ alkyl, C₄-C₉cycloalkyl, C₄-C₉ heterocycloalkyl, C₄-C₉ heterocycloalkylalkyl, aryl,mixed aryl and non-aryl polycycle, heteroaryl, arylalkyl, andheteroarylalkyl; R₁₃ and R₁₄ are the same or different and independentlyselected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, amino acyl, or R₁₃ and R₁₄together with the nitrogen to which they are bound are C₄-C₉heterocycloalkyl, heteroaryl, polyheteroaryl, non-aromaticpolyheterocycle or mixed aryl and non-aryl polyheterocycle; R₁₅ isselected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl and (CH₂)_(m)ZR₁₂; R₁₆ isselected from C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl,aryl, heteroaryl, polyheteroaryl, arylalkyl, heteroarylalkyl and(CH₂)_(m)ZR₁₂; R₁₇ is selected from C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉heterocycloalkyl, aryl, aromatic polycycle, heteroaryl, arylalkyl,heteroarylalkyl, polyheteroaryl and NR₁₃R₁₄; m is an integer selectedfrom 0 to 6; and Z is selected from O, NR₁₃, S and S(O); or apharmaceutically acceptable salt thereof.
 2. A compound of claim 1wherein each of R₁, X, Y, R₃, and R₄ is H.
 3. A compound of claim 2 oneof n₂ and n₃ is zero and the other is
 1. 4. A compound of claim 3wherein R₂ is H or —CH₂—CH₂—OH.
 5. A compound of claim 1 of the formula(Ia)

wherein n₄ is 0-3, R₂ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl,C₄-C₉ heterocycloalkyl, alkylcycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, —(CH₂)_(n)C(O)R₆, amino acyl and —(CH₂)_(n)R₇; R₅′ isheteroaryl, heteroarylalkyl, an aromatic polycycle, a non-aromaticpolycycle, a mixed aryl and non-aryl polycycle, polyheteroaryl, or amixed aryl and non-aryl polyheterocycle or a pharmaceutically acceptablesalt thereof.
 6. A compound of claim 1 of the formula (Ia)

wherein n₄ is 0-3, R₂ is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl,C₄-C₉ heterocycloalkyl, alkylcycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, —(CH₂)_(n)C(O)R₆, amino acyl and —(CH₂)_(n)R₇; R₅′ isaryl, arylalkyl, an aromatic polycycle, a non-aromatic polycycle or amixed aryl and non-aryl polycycle, or a pharmaceutically acceptable saltthereof.
 7. A compound of claim 6 wherein R₅′ is aryl or arylalkyl.
 8. Acompound of claim 7 wherein R₅′ is p-fluorophenyl, p-chlorophenyl,p-O—C₁-C₄-alkylphenyl, p-C₁-C₄-alkylphenyl, benzyl, ortho, meta orpara-fluorobenzyl, ortho, meta or para-chlorobenzyl, or ortho, meta orpara-mono, di or tri-O—C₁-C₄-alkylbenzyl.
 9. A compound of claim 1 offormula Ib:

wherein R₂′ is selected from H, C₁-C₆ alkyl, C₄-C₆ cycloalkyl,alkylcycloalkyl, and (CH₂)₂₋₄OR₂₁ where R₂₁ is H, methyl, ethyl, propyl,or isopropyl, and R₅″ is unsubstituted or substituted 1H-indol-3-yl,benzofuran-3-yl or quinolin-3-yl or a pharmaceutically acceptable saltthereof.
 10. A compound of claim 9 wherein R₅″ is substituted1H-indol-3-yl or substituted benzofuran-3-yl.
 11. A compound of claim 1of formula (Ic)

wherein the ring containing Z₁ is aromatic or non-aromatic whichnon-aromatic rings are saturated or unsaturated, Z₁ is O, S or N—R₂₀;R18 is H, halo, C₁-C₆alkyl, C₃-C₇cycloalkyl, aryl, or heteroaryl; R₂₀ isH, C₁-C₆alkyl, C₁-C₆alkyl-C₃-C₉cycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, acyl or sulfonyl; A₁ is 1, 2 or 3 substituents whichare independently H, C₁-C₆alkyl, —OR₁₉, halo, alkylamino, aminoalkyl,halo, or heteroarylalkyl, R₂ is selected from H, C₁-C₆ alkyl, C₄-C₉cycloalkyl, C₄-C₉ heterocycloalkyl, alkylcycloalkyl, aryl, heteroaryl,arylalkyl, heteroarylalkyl, —(CH₂)_(n)C(O)R₆, amino acyl and—(CH₂)_(n)R₇; R₁₉ is selected from H, C₁-C₆alkyl, C₄-C₉cycloalkyl,C₄-C₉heterocycloalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl;v is 0, 1 or 2, p is 0-3, and q is 1-5 and r is 0 or q is 0 and r is 1-5or a pharmaceutically acceptable salt thereof.
 12. A compound of claim11 wherein Z₁ is N—R₂₀.
 13. A compound of claim 11 wherein R₂ is H or—CH₂—CH₂—OH and the sum of q and r is
 1. 14. A compound of claim 1 ofthe formula (Id)

wherein Z₁ is O, S or N—R₂₀, R18 is H, halo, C₁-C₆alkyl,C₃-C₇cycloalkyl, unsubstituted phenyl, substituted phenyl, orheteroaryl, R₂₀ is H, C₁-C₆alkyl, C₁-C₆alkyl-C₃-C₉cycloalkyl, aryl,heteroaryl, arylalkyl, heteroarylalkyl, acyl or sulfonyl; A₁ is 1, 2 or3 substituents which are independently H, C₁-C₆alkyl, —OR₁₉, or halo,R₁₉ is selected from H, C₁-C₆alkyl, C₄-C₉cycloalkyl,C₄-C₉heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and—(CH₂CH═CH(CH₃)(CH₂))₁₋₃H; p is 0-3, and q is 1-5 and r is 0 or q is 0and r is 1-5, or a pharmaceutically acceptable salt thereof.
 15. Acompound of claim 14 wherein R₂ is H or —CH₂—CH₂—OH and the sum of q andr is
 1. 16. A compound of claim 11 of formula (Ie)

or a pharmaceutically acceptable salt thereof.
 17. A compound of claim16 wherein R18 is H, fluoro, chloro, bromo, a C₁-C₄alkyl group, aC₃-C₇cycloalkyl group, phenyl or a heteroaryl ring.
 18. A compound ofclaim 16 wherein R₂ is H, or —(CH₂)_(s)CH₂OH and wherein s is 1-3.
 19. Acompound of claim 18 wherein R₁ is H and X and Y are each H, and whereinq is 1-3 and r is or wherein q is 0 and r is 1-3.
 20. A compound ofclaim 16 wherein R18 is H, methyl, ethyl, t-butyl, trifluoromethyl,cyclohexyl, phenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 2-furanyl,2-thiophenyl, or 2-, 3- or 4-pyridyl.
 21. A compound of claim 20 whereinR₂ is H, or —(CH₂)_(s)CH₂OH and wherein s is 1-3.
 22. A compound ofclaim 21 wherein p is 1-3
 23. A compound of claim 22;wherein R₁ is H andX and Y are each H, and wherein q is 1-3 and r is 0 or wherein q is 0and r is 1-3.
 24. A compound of claim 23 wherein R₂ is H or —CH₂—CH₂—OHand the sum of q and r is
 1. 25. A compound of claim 16 wherein R₂₀ is Hor C₁-C₆alkyl.
 26. A compound of claim 16 selected from the groupconsisting ofN-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,N-hydroxy-3-[4-[[[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamideandN-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof.
 27. A compound of claim 1of the formula (If)

or a pharmaceutically acceptable salt thereof.
 28. A compound of claim27 wherein R₂ is H or —(CH₂)_(p)CH₂OH and p is 1-3.
 29. A compound ofclaim 28 wherein R₁ is H and X and Y are each H, and wherein q is 1-3and r is 0 or wherein q is 0 and r is 1-3.
 30. A compound of claim 29wherein R₂ is H or —CH₂—CH₂—OH and the sum of q and r is
 1. 31. Acompound of claim 27 which isN-hydroxy-3-[4-[[[2-(benzofur-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof.
 32. A pharmaceuticalcomposition comprising a pharmaceutically effective amount of a compoundof formula (I)

wherein R₁ is H, halo, or a straight chain C₁-C₆ alkyl; R₂ is selectedfrom H, C₁-C₁₀ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl, C₄-C₉heterocycloalkylalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, —(CH₂)_(n)C(O)R₆, —(CH₂)_(n)OC(O)R₆, amino acyl,HON—C(O)—CH═C(R₁)-aryl-alkyl- and —(CH₂)_(n)R₇; R₃ and R₄ are the sameor different and independently H, C₁-C₆ alkyl, acyl or acylamino, or R₃and R₄ together with the carbon to which they are bound represent C═O,C═S, or C═NR₈, or R₂ together with the nitrogen to which it is bound andR₃ together with the carbon to which it is bound can form a C₄-C₉heterocycloalkyl, a heteroaryl, a polyheteroaryl, a non-aromaticpolyheterocycle, or a mixed aryl and non-aryl polyheterocycle ring; R₅is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉heterocycloalkyl, acyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,aromatic polycycle, non-aromatic polycycle, mixed aryl and non-arylpolycycle, polyheteroaryl, non-aromatic polyheterocycle, and mixed aryland non-aryl polyheterocycle; n, n₁, n₂ and n₃ are the same or differentand independently selected from 0-6, when n, is 1-6, each carbon atomcan be optionally and independently substituted with R₃ and/or R₄; X andY are the same or different and independently selected from H, halo,C₁-C₄ alkyl, NO₂, C(O)R₁, OR₉, SR₉, CN, and NR₁₀R₁₁; R₆ is selected fromH, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl,cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, OR₁₂, andNR₁₃R₁₄; R₇ is selected from OR₁₅, SR₁₅, S(O)R₁₆, SO₂R₁₇, NR₁₃R₁₄, andNR₁₂SO₂R₆; R₈ is selected from H, OR₁₅, NR₁₃R₁₄, C₁-C₆ alkyl, C₄-C₉cycloalkyl, C₄-C₉ heterocycloalkyl, aryl, heteroaryl, arylalkyl, andheteroarylalkyl; R₉ is selected from C₁-C₄ alkyl and C(O)-alkyl; R₁₀ andR₁₁ are the same or different and independently selected from H, C₁-C₄alkyl, and —C(O)-alkyl; R₁₂ is selected from H, C₁-C₆ alkyl, C₄-C₉cycloalkyl, C₄-C₉ heterocycloalkyl, C₄-C₉ heterocycloalkylalkyl, aryl,mixed aryl and non-aryl polycycle, heteroaryl, arylalkyl, andheteroarylalkyl; R₁₃ and R₁₄ are the same or different and independentlyselected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, amino acyl, or R₁₃ and R₁₄together with the nitrogen to which they are bound are C₄-C₉heterocycloalkyl, heteroaryl, polyheteroaryl, non-aromaticpolyheterocycle or mixed aryl and non-aryl polyheterocycle; R₁₅ isselected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl and (CH₂)_(m)ZR₁₂; R₁₆ isselected from C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl,aryl, heteroaryl, polyheteroaryl, arylalkyl, heteroarylalkyl and(CH₂)_(m)ZR₁₂; R₁₇ is selected from C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉heterocycloalkyl, aryl, aromatic polycycle, heteroaryl, arylalkyl,heteroarylalkyl, polyheteroaryl and NR₁₃R₁₄; m is an integer selectedfrom 0 to 6; and Z is selected from 0, NR₁₃, S and S(O); or apharmaceutically acceptable salt thereof.
 33. A pharmaceuticalcomposition of claim 32 wherein the compound of formula (I) is selectedfrom the group consisting of selectedN-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,N-hydroxy-3-[4-[[[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamideandN-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof.
 34. A pharmaceuticalcomposition of claim 32 which isN-hydroxy-3-[4-[[[2-(benzofur-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof.
 35. A method for treatinga proliferative disorder in a mammal which comprises administering tosaid mammal a compound of the formula (I)

wherein R₁ is H, halo, or a straight chain C₁-C₆ alkyl; R₂ is selectedfrom H, C₁-C₁₀ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl, C₄-C₉heterocycloalkylalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, —(CH₂)_(n)C(O)R₆, —(CH₂)_(n)OC(O)R₆, amino acyl,HON—C(O)—CH═C(R,)-aryl-alkyl- and —(CH₂)_(n)R₇; R₃ and R₄ are the sameor different and independently H, C₁-C₆ alkyl, acyl or acylamino, or R₃and R₄ together with the carbon to which they are bound represent C═O,C═S, or C═NR₈, or R₂ together with the nitrogen to which it is bound andR₃ together with the carbon to which it is bound can form a C₄-C₉heterocycloalkyl, a heteroaryl, a polyheteroaryl, a non-aromaticpolyheterocycle, or a mixed aryl and non-aryl polyheterocycle ring; R₅is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉heterocycloalkyl, acyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,aromatic polycycle, non-aromatic polycycle, mixed aryl and non-arylpolycycle, polyheteroaryl, non-aromatic polyheterocycle, and mixed aryland non-aryl polyheterocycle; n, n₁, n₂ and n₃ are the same or differentand independently selected from 0-6, when n, is 1-6, each carbon atomcan be optionally and independently substituted with R₃ and/or R₄; X andY are the same or different and independently selected from H, halo,C₁-C₄ alkyl, NO₂, C(O)R₁, OR₉, SR₉, CN, and NR₁₀R₁₁; R₆ is selected fromH, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl,cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, OR₁₂, andNR₁₃R₁₄; R₇ is selected from OR₁₅, SR₁₅, S(O)R₆, SO₂R, NR₁₃R₁₄, andNR₁₂SO₂R; R₈ is selected from H, OR₁₅, NR₁₃R₁₄, C₁-C₆ alkyl, C₄-C₉cycloalkyl, C₄-C₉ heterocycloalkyl, aryl, heteroaryl, arylalkyl, andheteroarylalkyl; R₉ is selected from C₁-C₄ alkyl and C(O)-alkyl; R₁₀ andR₁₁ are the same or different and independently selected from H, C₁-C₄alkyl, and —C(O)-alkyl; R₁₂ is selected from H, C₁-C₆ alkyl, C₄-C₉cycloalkyl, C₄-C₉ heterocycloalkyl, C₄-C₉ heterocycloalkylalkyl, aryl,mixed aryl and non-aryl polycycle, heteroaryl, arylalkyl, andheteroarylalkyl; R₁₃ and R₁₄ are the same or different and independentlyselected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, amino acyl, or R₁₃ and R₁₄together with the nitrogen to which they are bound are C₄-C₉heterocycloalkyl, heteroaryl, polyheteroaryl, non-aromaticpolyheterocycle or mixed aryl and non-aryl polyheterocycle; R₁₅ isselected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl and (CH₂)_(m)ZR₁₂; R₁₆ isselected from C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl,aryl, heteroaryl, polyheteroaryl, arylalkyl, heteroarylalkyl and(CH₂)_(m)ZR₁₂; R₁₇ is selected from C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉heterocycloalkyl, aryl, aromatic polycycle, heteroaryl, arylalkyl,heteroarylalkyl, polyheteroaryl and NR₁₃R₁₄; m is an integer selectedfrom 0 to 6; and Z is selected from O, NR₁₃, S and S(O); or apharmaceutically acceptable salt thereof.
 36. A method of claim 35wherein the compound of formula (I) is selected from the groupconsisting ofN-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,N-hydroxy-3-[4-[[[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamideandN-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof.
 37. A method forregulating p21 promoter which comprises introducing a compound of theformula (I)

wherein R₁ is H, halo, or a straight chain C₁-C₆ alkyl; R₂ is selectedfrom H, C₁-C₁₀ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl, C₄-C₉heterocycloalkylalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, —(CH₂)_(n)C(O)R₆, —(CH₂)_(n)OC(O)R₆, amino acyl,HON—C(O)—CH═C(R₁)-aryl-alkyl- and —(CH₂)_(n)R₇; R₃ and R₄ are the sameor different and independently H, C₁-C₆ alkyl, acyl or acylamino, or R₃and R₄ together with the carbon to which they are bound represent C═O,C═S, or C═NR₈, or R₂ together with the nitrogen to which it is bound andR₃ together with the carbon to which it is bound can form a C₄-C₉heterocycloalkyl, a heteroaryl, a polyheteroaryl, a non-aromaticpolyheterocycle, or a mixed aryl and non-aryl polyheterocycle ring; R₅is selected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉heterocycloalkyl, acyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,aromatic polycycle, non-aromatic polycycle, mixed aryl and non-arylpolycycle, polyheteroaryl, non-aromatic polyheterocycle, and mixed aryland non-aryl polyheterocycle; n, n₁, n₂ and n₃ are the same or differentand independently selected from 0-6, when n₁ is 1-6, each carbon atomcan be optionally and independently substituted with R₃ and/or R₄; X andY are the same or different and independently selected from H, halo,C₁-C₄ alkyl, NO₂, C(O)R₁, OR₉, SR₉, CN, and NR₁₀R₁₁; R₆ is selected fromH, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl,cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, OR₁₂, andNR₁₃R₁₄; R₇ is selected from OR₁₅, SR₁₅, S(O)R₁₆, SO₂R₁₇, NR₁₃R₁₄, andNR₁₂SO₂R₆; R₈ is selected from H, OR₁₅, NR₁₃R₁₄, C₁-C₆ alkyl, C₄-C₉cycloalkyl, C₄-C₉ heterocycloalkyl, aryl, heteroaryl, arylalkyl, andheteroarylalkyl; R₉ is selected from C₁-C₄ alkyl and C(O)-alkyl; R₁₀ andR₁₁ are the same or different and independently selected from H, C₁-C₄alkyl, and —C(O)-alkyl; R₁₂ is selected from H, C₁-C₆ alkyl, C₄-C₉cycloalkyl, C₄-C₉ heterocycloalkyl, C₄-C₉ heterocycloalkylalkyl, aryl,mixed aryl and non-aryl polycycle, heteroaryl, arylalkyl, andheteroarylalkyl; R₁₃ and R₁₄ are the same or different and independentlyselected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, amino acyl, or R₁₃ and R₁₄together with the nitrogen to which they are bound are C₄-C₉heterocycloalkyl, heteroaryl, polyheteroaryl, non-aromaticpolyheterocycle or mixed aryl and non-aryl polyheterocycle; R₁₅ isselected from H, C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl and (CH₂)_(m)ZR₁₂; R₁₆ isselected from C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉ heterocycloalkyl,aryl, heteroaryl, polyheteroaryl, arylalkyl, heteroarylalkyl and(CH₂)_(m)ZR₁₂; R₁₇ is selected from C₁-C₆ alkyl, C₄-C₉ cycloalkyl, C₄-C₉heterocycloalkyl, aryl, aromatic polycycle, heteroaryl, arylalkyl,heteroarylalkyl, polyheteroaryl and NR₁₃R₁₄; m is an integer selectedfrom 0 to 6; and Z is selected from O, NR₁₃, S and S(O); or apharmaceutically acceptable salt thereof, into the environment of amammalian cell.
 38. A method of claim 37 wherein the compound of formula(I) is selected from the group consisting ofN-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,N-hydroxy-3-[4-[[[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamideandN-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof.